review Neuromuscular Blockade in the Intensive Care Unit* Douglas A. Isenstein, M.D., EG.G.P.; Debra S. and Jane Duggan, M.D. t (Chest 1992; 102:1258-66)

leu = intensive

care unit; NMBA = neuromuscular blocking

agent

blocking agents (NMBAs) are used N euromuscular in the intensive care unit (ICU) to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. To ensure proper use of NMBAs, the risks, benefits, and characteristics of individual agents must be understood. This article will review the mechanism of action , dosages, metabolism, comFor editorial comment see page 1258 plications, and drug interactions of the most commonly used NMBAs. In addition, indications for use in the ICU and necessary monitoring will also be discussed. The first description of the use of neuromuscular blockade was in 1932, when curare was given to control muscle spasms of tetanus. I Since then, the pharmacology of these drugs has developed and expanded exponentially. Despite tremendous advances and development of new agents, the perfect NMBA has not yet been discovered. Such an agent would possess the following characteristics: rapid onset of action, predictable and controllable duration of action, no hemodynamic consequences, predictable kinetics (independent of age, gender, body temperature, and body habitus of the patient), no active metabolites, no toxicity, nondepolarizing, and elimination independent of hepatic or renal function. The NMBAs are classified as either depolarizing or nondepolarizing (Table 1). The nondepolarizing agents may be further categorized by duration as either intermediate or longacting. This family of drugs resembles acetylcholine in that each has one or more positively charged quaternary ammonium groups, which are attracted to the negatively charged cholinergic receptor. From a structureactivity perspective, the nondepolarizing agents may ·From the Department of Medicine, Humana Hospital Gwinnett, Snellville, Ga (Dr Isen stein): and the Department of Anesthe siology, Emory University School of Medicine, Atlanta (Drs Venner and Duggan ). t Assistant Professor of Anesthesiology. Reprint requests: Dr. lknner, Department of Anesthesia , 1364 Clifton Road, EN, Atlanta 30322

1258

~nner,

M.D.;t

also be divided into two categories: steroidal compounds (eg, pancuronium, vecuronium , pipecuronium) and benzylisoquinolines (eg, mivacurium , atracurium). DEPOLARIZING NMBAs Succinylcholine is currently the only depolarizing agent in widespread use. It is a short-acting NMBA that works rapidly to facilitate tracheal intubation.

Mechanism of Action Succinylcholine binds to the acetylcholine receptor and causes persistent depolarization of the neuromuscular motor end plate, which then spreads to the muscle and causes muscle contraction. This persistent depolarization prevents propagation of the action potential, and muscle weakness results.2(p177} Muscle contraction cannot return to full strength until succinylcholine is metabolized .

Metabolism, Dose, and Duration of Action Metabolism of succinylcholine occurs as a result of the enzyme plasma cholinesterase (pseudocholinesterase). After an intubating dose (1 to 1.5 rng/kg intravenously), neuromuscular blockade occurs within 1 to 1.5 min, and recovery occurs within 10 to 15 min ." There are a variety of medical conditions that can affect the metabolism of succinylcholine and its duration of action . The enzyme pseudocholinesterase Table I-Classification o/Neuromuscular Blocking Drugs· Depol arizers Succinylcholine Decameth onium Nondepo larize rs Long -acting

Tubocu rarine Met ocurine Gallamine Pancuronium Doxacu riurn

Pipecuronium Intermediate-acting Atr acu riurn Veeu ron ium

Mivacurium *Modified from referenc e 2 (p 172). Neuromuscular Blockade in the leu (/senstein, Venner. Duggan)

is synthesized in the liver, and low enzyme levels may occur in patients with hepatic disease, in neonates, and in normal subjects during pregnancy. There are also cases in which the enzyme itself may be congenitally nonfunctional or deficient. In addition, patients with severe anemia, malignancy, and certain connective tissue disorders may also have a prolonged block from succinylcholine secondary to low plasma levels of pseudocholinesterase. 4 Renal dialysis may diminish the plasma levels of pseudocholinesterase as well.

Silk Effects Succinylcholine is known to cause a variety of adverse side effects, which are of great concern in an ICU. Succinylcholine may cause an efflux of potassium from cells, which may transiently elevate the serum potassium concentration by 0.5 to 1.0 mEq/L. In healthy patients, this does not pose a significant problem. In some situations, however, muscle fasciculations associated with succinylcholine may cause a substantial rise in serum potassium, myoglobin, and creatinine phosphokinase. The large increase in plasma potassium levels can result in serious cardiac dysrhythmias and even cardiac collapse or arrest." Hyperkalemia after succinylcholine administration is a serious risk in patients with extensive burns, upper motor lesions, skeletal muscle atrophy, and severe intra-abdominal infections. It is, therefore, not advisable to use succinylcholine in a patient with a spinal cord injury after the first 24 h. The risk of ventricular fibrillation or cardiac arrest after the use of succinylcholine may persist for six months or longer after injury in these patients," Frequently, a subparalytic dose of an NMBA is administered prior to succinylcholine to reduce fasciculations and muscle pains associated with succinylcholine, 7 but this so-called precurarization does not reduce the increase in serum potassium concentration." Succinylcholine can cause an increase in intraocular pressure. This increase is thought to be mediated by prolonged tonic contractions of the extraocular muscles. It probably should be avoided in patients with open eye injuries and some types of glaucoma, because of the risk of vitreous expulsion and resulting blindness. Studies evaluating the increase in intraocular pressure by pretreatment with nondepolarizing muscle relaxants are contradictory. 9 Although the mechanism is not completely known, succinylcholine has been shown to increase intracranial pressure, and should be used judiciously in patients with brain tumors or cerebral edema.'? Due to stimulation of either the parasympathetic or sympathetic autonomic nervous systems, succinylcholine can cause either bradycardia (more common in children) or tachycardia (more common in adults)." Succinylcholine has been identified as a triggering

agent for malignant hyperthermia. This hypermetabolic state can cause respiratory and circulatory collapse resulting in death. 11 Another potential complication of the use of succinylcholine is the development of a profound longlasting neuromuscular junction blockade known as a phase II block. This is usually seen after a large dose of succinylcholine is given over a prolonged period of time. Antagonism of a phase II block with an anticholinesterase is not reliable, and controversy exists as to whether to reverse the block or to let it wear off spontaneously 12 NONDEPOLARIZING NMBAs

Mechanism of Action Nondepolarizing NMBAs bind to the postsynaptic nicotinic cholinergic receptors on the motor end plate. They inhibit acetylcholine from binding to the neuromuscular receptor, thereby resulting in neuromuscular blockade. Because of their competitive mechanism of action, the effects of these drugs can be reversed with an acetylcholinesterase inhibitor, such as neostigmine, physostigmine, or edrophonium.P The reversal agent will increase acetylcholine at both the nicotinic and the muscarinic cholinergic junctions. Therefore, an anticholinergic drug, such as atropine or glycopyrrolate, should accompany the acetylcholinesterase inhibitor to prevent muscarinic side effects, such as salivation, bradycardia, and potential cardiac standstill. Neostigmine and pyridostigmine both require atropine, 15 JLglkg,14 whereas edrophonium requires less atropine, 7 ug/kg, 15 to prevent the muscarinic effects. Glycopyrrolate in doses of 7 JLglkg can be used with neostigmine and pyridostigmine, since the delayed vagal effects closely match the onset of action of those anticholinesterase drugs," but is not recommended in conjunction with edrophonium because of the potential for severe bradycardia.

Metabolism The decision to use a specific NMBA should be based on a variety of factors, which include duration of action, avoidance of side effects, and existing compromise of a particular organ system. Requirements for NMBAs may increase or decrease in the ICU over time. These changes may be due to changes in volume of distribution, receptor affinity, or enzyme induction 17 or to changes in metabolism or excretion. Therefore, careful attention must be paid to the degree of blockade, and constant assessment by means of a neuromuscular blockade monitor is necessary. Metabolism of each nondepolarizing agent varies from drug to drug (Table 2). Atracurium is metabolized by both Hofmann elimination (pH- and temperaturedependent) and ester hydrolysis. Prolonged duration of an atracurium-induced neuromuscular block in a CHEST I 102 I 4 I OCTOBER, 1992

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Table 2-Renal Elimination ofNondepolarizing Muscle Relaxants· Renal Elimination, %

Agents

>90

Gallamine Pancuronium, pipecuronium, doxacurium Tubocurarine, metocurine Vecuronium, t atracurium.j mivacurium

60-90 40-60

Neuromuscular blockade in the intensive care unit.

• review Neuromuscular Blockade in the Intensive Care Unit* Douglas A. Isenstein, M.D., EG.G.P.; Debra S. and Jane Duggan, M.D. t (Chest 1992; 102:12...
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